Hepatitis C virus (HCV) chronically infects millions people worldwide. The high genetic variability of the HCV genome enables evasion of host immune responses. Infection leads to chronic liver disease, cirrhosis, and sometimes hepatocellular carcinoma. The only approved treatment is combination therapy with pegylated interferon and ribavirin, which has various efficacies depending upon the genotype and the initial viral load. Thus, there is a need to identify improved methods of treating or preventing HCV infections.
HCV is a positive-sense, single-stranded RNA with a single open reading frame encoding a polypeptide that is processed into 10 separate proteins. The N-terminal region of the polypeptide is cleaved providing virus particle core, C, envelope proteins E1 and E2, and a putative ion channel (p′7). The non-structural proteins are believed to be NS2, NS3, NS4A, NS4B, NS5A, and NS5B.
The HCV envelope protein E2 is in the outer shell of the virus particle and suggested to interact with several cellular receptors including CD81, scavenger receptor class B type I (SR-BI), claudin-1, and occludin. The binding of hepatitis C virus glycoprotein E2 to the large extracellular loop (LEL) of CD81 has been suggested to modulate human T-cell and NK cell activity in vitro. Using random mutagenesis of a chimera of maltose-binding protein and LEL, Drummer et al., J. Virol., 2002, 76(21) 11143-11147, determined an E2-binding site on CD81. Whidby et al., Journal of Virology, 2009, 83(21), 11078-11089 disclose that a recombinant form of Envelope Protein 2 Ectodomain blocks Hepatitis C Virus Infection.
Disulfide bonds have been shown to effect stability of complexes formed by E1 and E2 in extracellular HCV viral particles. See Vieyres et al., J. Virol., 2010, 84(19):10159-10168; Fraser et al., J Biol Chem., 2011, 286(37):31984-92; and McCaffery et al., J. Virol., 2011, 92:112-121.
See also GenBank Accession No. BAB32875.1 and GenBank: ACY38785.1.
References cited herein are not an admission of prior art.